Targeting Chronic and Age-Related Diseases
Clinical Program: CB4211 for NASH & Obesity
Our first clinical candidate, CB4211, is a potential treatment for nonalcoholic steatohepatitis (NASH) and obesity. It is a novel peptide developed from the MDP MOTS-c.
In August 2021, we released positive topline data from our Phase 1a/1b clinical study of CB4211. The Phase 1a stage of the study was designed to initially assess the safety, tolerability and pharmacokinetics of CB4211 following single and multiple-ascending doses in 65 healthy subjects. The Phase 1b stage was designed to assess the safety, tolerability and activity of CB4211 delivered once daily compared to placebo over a four-week period in 20 obese subjects with non-alcoholic fatty liver disease. Exploratory endpoints included changes in liver fat assessed by magnetic resonance imaging – proton density fat fraction (MRI-PDFF), body weight and biomarkers relevant to NASH and obesity.
The study met its primary endpoints as CB4211 was well-tolerated and appeared safe with no serious adverse events. The evaluation of the exploratory endpoints showed significant reductions from baseline in key biomarkers of liver damage, ALT and AST, and in glucose levels in the CB4211 group compared to placebo after four weeks of treatment, with a trend towards lower body weight. At four weeks, ALT decreased by 21% from baseline for subjects treated with CB4211 compared to a 4% increase for placebo (p <0.05). The proportion of ALT responders achieving a >17 U/L decrease from baseline in ALT was 27% for subjects treated with CB4211 compared to 11% for subjects treated with placebo. A decrease of >17 U/L in ALT has been associated with histologic improvement in NASH patients. AST decreased by 28% from baseline for subjects treated with CB4211 compared to an 11% decrease for placebo (p <0.05). Glucose decreased by 6% from baseline for subjects treated with CB4211 compared to no change for placebo (p <0.05). There was a substantial reduction in absolute liver fat measured by MRI-PDFF in both treatment arms. By 4 weeks, liver fat showed an absolute decrease of 5.21% for CB4211 and an absolute decrease of 4.88% in placebo. The proportion of responders achieving at least a 30% reduction from baseline in liver fat content at four weeks was 36% for subjects treated with CB4211 compared to 33% for placebo. A relative reduction of 30% in liver fat is associated with a histological response in non-alcoholic steatohepatitis. Absolute liver fat decreased substantially in both treatment arms potentially due to subjects being confined during the treatment period on a standardized diet. We are continuing to analyze the data from the study, including the pharmacokinetic data when available.
Preclinical Programs
CB5138 Analogs for Idiopathic Pulmonary Fibrosis (IPF) and other Fibrotic Diseases: Our discovery efforts have identified CB5138 Analogs, a family of novel peptides with potential for use as treatments for fibrotic diseases. In co-cultures of human lung cells, CB5138-1 decreased the expression of key fibrosis biomarkers, including alpha smooth muscle actin (αSMA), and collagen types I and III. CB5138-1 also decreased the transformation of healthy lung cells into fibrotic cells after induction by TGFβ, resulting in reduced production of the fibrotic markers αSMA and pro-collagen I alpha 1. In vivo, CB5138-1 decreased lung fibrosis and inflammation in both the prophylactic mouse model of IPF, where treatment with the peptide is initiated immediately after fibrosis induction by bleomycin, and in the therapeutic mouse model of IPF, with peptide treatment starting one week after bleomycin induction. In the same therapeutic mouse model of IPF, a related analog of CB5138 (CB5138-3) significantly reduced lung fibrosis assessed by the Ashcroft Score, reduced inflammation measured by lymphocytes in lung fluid, and decreased fibrosis-related changes in lung weight, collagen deposition in lung tissue, and collagen secretion into lung fluid. CB5138-3 also demonstrated significant reductions in a wide range of pro-inflammatory cytokines in lung fluid in the therapeutic IPF model, compared to no change in these cytokines with nintedanib, one of the leading treatments for IPF. In the first quarter of 2021, we identified CB5138-3 as the lead clinical candidate in this program and we are currently conducting IND-enabling activities with the goal of filing an IND and initiating our First-in-Human study for this program in 2022.
CB5064 Analogs for Acute Respiratory Distress Syndrome (ARDS), including COVID-19 Associated ARDS: Our internal discovery efforts have identified CB5064 Analogs, a family of peptides that are agonists of the apelin receptor with potential for use as therapeutics for COVID-19 associated ARDS and ARDS in general. In May 2020, we initiated testing of CB5064 Analogs in preclinical models of ARDS. In these studies, acute lung injury was induced in mice by administration of lipopolysaccharide (LPS), a bacterial toxin that produces similar symptoms to other causes of ARDS, including fluid accumulation and cytokine secretion in the lung. A single dose of CB5064 Analog was administered one hour prior to the LPS exposure and effects on lung weight and levels of pro-inflammatory cytokines were measured at 4 hours after LPS exposure. Treatment with CB5064 Analogs reduced fluid accumulation in the lungs and a corresponding broad reduction in levels of key pro-inflammatory cytokines secreted into the lung fluid, when compared to treatment with a placebo control. With additional funding, we expect to be in a position to nominate a clinical candidate for this program and initiate additional IND-enabling work, with the longer-term goal of initiating a Phase 1 study.
CB5046 Analogs for Cancer and Other Disease Indications: Our internal discovery efforts have identified CB5046 Analogs, a family of novel potent and selective peptide inhibitors of CXCR4, a key chemokine receptor involved in tumor growth, metastasis and avoidance of immune surveillance that is overexpressed in 75% of human tumors. CXCR4 is also involved in localization of healthy stem cells and in certain genetic diseases. We have demonstrated positive effects of one of our CB5046 Analogs when administered in combination with chemotherapy in an animal model of aggressive melanoma.
MBT3 Analogs for Cancer Immunotherapy: Our discovery efforts identified a novel peptide family, MBT3 Analogs. We have demonstrated the enhanced killing of cancer cells by human immune cells in the presence of an MBT3 Analog, and plan to further explore the therapeutic potential of this analog family for treatment of cancer, subject to resource availability and the requirements of our more-advanced programs.
CohBar Peptide Library
Our discovery efforts have resulted in the identification of more than 100 previously unidentified peptides encoded within the mitochondrial genome and we have generated over 1,000 analogs. We continue to explore the broad biological effects of these peptides and their potential application as novel therapeutics. Our criteria include examining MDP analogs with the greatest commercial and therapeutic potential, the most suitable development and clinical resources, and the broadest intellectual property protection and exploitation opportunities.